The invention relates to the use of anellated dihydropyridines and the salts thereof with physiologically acceptable acids for preparing agents for the treatment of chronic pain.
EP 0 491 441 A1, describes the compound of Formula 
wherein ZR6 denotes para-phenoxy. There is no reference therein to the treatment of chronic pain.
British Patent 2236674 describes compounds for treating pain and/or CNS-diseases in which R4 and R5 denote hydrogen, Z denotes a bond and R6 denotes a C1-C5 alkyl, aryl or aryl-lower alkyl group. These compounds act as GABA antagonists on GABA-autoreceptors.
Diseases connected with chronic or chronically recurring pain include, inter alia, migraine, neuralgia, muscle pain and inflammatory pain. They have mechanisms in common with chronically recurring pain [Dray, A. Urban L. and Dickenson, A. Trends in Pharmacological Sciences 1994; 15:190-197].
The chronic neuronal pains include inter alia postoperative pain, shingles, phantom pain, diabetic neuropathy, pain after chronic nerve compression as well as AIDS and cancer in their final stages.
The aim of the present invention is to provide an active substance for treating chronic pain, particularly chronic neuronal pain, with good bioavailability and a powerful antinociceptive activity.
In one general aspect, the present invention is directed to a method of treating chronic pain by the administration of a compound of formula I or a pharmaceutically acceptable salt thereof: 
wherein A is benzo or thieno,
and if A is benzo
R1, R2 and R3 independently of one another denote
H, OH, C1-C5 alkyl, C1-C5 alkoxy, xe2x80x94Oxe2x80x94(CH2)1-5xe2x80x94OCH3 
or R2 and R3 together form the group
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, and
if A is thieno, R1, R2 and R3 denote hydrogen;
R4 and R5 independently of one another denote
H, C1-C5 alkyl or
Together with the central atom to which they are bonded form a C3-C7 ring.
R6 denotes C1-C12 alkyl or a phenyl or benzyl group substituted by the groups R7 and R8,
wherein R7 and R8 independently of one another denote hydrogen, halogen (F, Cl, Br, I), C1-C5 alkyl, C1-C5 alkoxy or C1-C5 fluoroalkyl group.
Z denotes O, S or an NHCOxe2x80x94 group or, if at least one of the groups R4 and R5 is other than hydrogen, Z may also denote a single bond.
In a second general aspect, the present invention is directed to a compound of formula I above, or a pharmaceutically acceptable salt thereof, with the proviso that the compound of the following formula: 
wherein ZR6=para-phenoxy is excluded. The present invention is also directed to pharmaceutical compositions comprising these compounds of formula I or a pharmaceutically acceptable salt thereof.
Surprisingly, the compounds according to the present invention exhibit a powerful antinociceptive activity based on the blockade of voltage-dependent N-type Ca+2-channels.
The invention therefore relates to the use of the compounds of Formula I, or the salts thereof with physiologically acceptable acids, for the preparation of a pharmaceutical composition for treating chronic pain: 
wherein A is benzo or thieno,
and if A is benzo
R1, R2 and R3 independently of one another denote
H, OH, C1-C5 alkyl, C1-C5 alkoxy, xe2x80x94Oxe2x80x94(CH2)1-5xe2x80x94OCH3 
or R2 and R3 in positions 6 and 7 together form the group
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, and
if A is thieno, R1, R2 and R3 denote hydrogen;
R4 and R5 independently of one another denote
H, C1-C5 alkyl or
together with the central atom to which they are bonded form a C3-C7 ring.
R6 denotes C1-C12 alkyl or a phenyl or benzyl group substituted by the groups R7 and R8,
wherein R7 and R8 independently of one another denote hydrogen, halogen (F, Cl, Br, I), C1-C5 alkyl, C1-C5 alkoxy or C1-C5 fluoroalkyl group.
Z denotes O, S or an NHCOxe2x80x94 group or, if at least one of the groups R4 and R5 is other than hydrogen, Z may also denote a single bond.
The invention further relates to the compounds of Formula I above, with the proviso that the compound of the following formula: 
wherein ZR6=para-phenoxy is excluded.
Preferred compounds are the compounds of Formula IA and their use as described above, 
wherein R1, R2 and R3 preferably independently of one another denote hydrogen, methyl or methoxy, particularly wherein R2 and R3 denote methoxy and R1 is methoxy or hydrogen.
Also preferred are compounds of general Formula I and their use as specified above wherein R4 and R5 independently of each other denote hydrogen or a methyl group.
Particularly preferred are compounds of general Formula I and their use as described above, wherein Zxe2x80x94R6 denotes a group of general Formula II, III or IV: 
Particularly preferred are compounds of general Formula I and their use as described above wherein R6 denotes C6-C10 alkyl.
Additional embodiments are compounds of general Formula I and their use as described above, wherein Zxe2x80x94R6 denotes a phenoxy group of formula II in the ortho or para-position;
Additional embodiments are compounds of general Formula I and their use as described above, wherein at least one of the groups R7 and R8 denotes a CF3 group or an F atom.
Additional embodiments are compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula: 
wherein R4 and R5 simultaneously denote hydrogen or methyl, and R6 denotes a group of formula V, VI or VII: 
Additional embodiments are compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula: 
wherein R1 denotes methyl or methoxy, R4 and R5 simultaneously denote hydrogen or methyl, and R6 denotes a group of formula V or VII: 
An additional embodiment is compounds of general Formula I and their use as described above, wherein the compound of formula I is a compound of the following formula: 
Another general aspect of the invention is directed to a compound of the following formula I, or a pharmaceutically acceptable salt thereof: 
wherein A is benzo or thieno,
and if A is benzo
R1, R2 and R3 independently of one another denote
H, OH, C1-C5 alkyl, C1-C5 alkoxy, xe2x80x94Oxe2x80x94(CH2)1-5xe2x80x94OCH3,
or R2 and R3 together form the group
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, and
if A is thieno, R1, R2 and R3 denote hydrogen;
R4 and R5 independently of one another denote
H, C1-C5 alkyl or together with the atom to which they are bonded form a C3-C7 ring;
R6 denotes C1-C12 alkyl, or denotes a phenyl or benzyl group each substituted by the groups R7 and R8,
wherein R7 and R8 independently of one another denote hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy or C1-C5 fluoroalkyl group;
Z denotes O, S or an NHCOxe2x80x94 group or, if at least one of the groups R4 and R5 is other than hydrogen, Z may also denote a single bond.
with the proviso that the compound of the following formula is excluded: 
wherein ZR6=para-phenoxy.
One embodiment is directed to a compound of formula I above, or a pharmaceutically acceptable salt thereof, wherein Zxe2x80x94R6 denotes a group of formula II or IV: 
Another embodiment is directed to a compound of formula I above, wherein R4 and R5 simultaneously denote hydrogen or methyl, and R6 denotes a group of formula V, VI or VII: 
Another embodiment is directed to a compound of formula I above, wherein the compound has the following formula: 
wherein R methyl or methoxy, R4 and R5 simultaneously denote hydrogen or methyl and R6 denotes a group of formula V or VII: 
Another embodiment is directed to a pharmaceutical composition comprising a compound of formula I described above.
Acids suitable for forming the salts of the compounds according to the invention include, for example, hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulphonic acid.
The term alkyl groups denotes branched and unbranched alkyl groups having 1 to 12, preferably 2 to 10, most preferably 5 to 6 carbon atoms, including, for example: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl and n-hexyl, but also n-decyl.
The term alkoxy groups denotes branched and unbranched alkoxy groups having 1 to 5 carbon atoms, including for example: methyloxy, ethyloxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec. butyloxy, tert.-butyloxy, n-pentyloxy, iso-pentyloxy and neo-pentyloxy.
The term cycloalkyl groups having 3 to 7 carbon atom denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term fluoroalkyl groups denotes branched and unbranched fluoroalkyl groups having 1 to 5 carbon atoms and 1 to the maximum possible number of fluorine atoms, preferably 1,1,1-trifluoroethyl, most preferably trifluoromethyl.
The compounds according to the invention are intended to be illustrated by the Examples which follow. The skilled person will be aware that the Examples are intended solely as an illustration and not to be regarded as limiting.